The invention relates to medicaments with prostaglandin-synthetases inhibiting activity.
Prostaglandins (PGS) are widely present in all mammalian organisms Only in recent years scientific research has made intensive efforts for extracting the biological activity of prostaglandins and acquiring knowledge thereof. According to present knowledge multiple PGS or precursors exists which vary somewhat in structure and have biological importances of wide spread occurrence, high activities and differences in metabolic action. These different actions are based on the fact that the intracellular PG synthesis can be induced by irritation or damage of cellular membranes during which in the first phase phospho-lipases release PG-precursors from membrane lipides, or that on the other hand several hormones e.g, bradykinines, acetylcholin or histamine increase the synthesis and release of PGS and that moreover PGS not only stimulate the adenyl-cylase system but the guanyl-cyclase-system also and therefore can cause an increase of intracellular APM-and GPM-concentrations.
It has already been known that the PG effects vary depending on the PG types used and the tested organs, e.g., the adenyl-cyclase is stimulated in endocrine organs by PGE.sub.1 and PGE.sub.2 but inhibited in fat tissue. This fact explains why PGS are able to increase or decrease the APM level in a target organ and display an adrenaline-and glycogen antagonistic effect in fat tissue. With smooth muscles PGS effect partly contractions e.g. in the uterus or intestine or dilatation e.g. in blood vessels. PGS E.sub.2 and A.sub.2 increase secretion of sodium and potassium in the kidney. Furthermore, it had been established already that an increase of PGS E.sub.2 and F.sub.2 level in the tissue can initiate and maintain inflammatory reactions.
The multiple metabolic effects of PGS are the basis for several therapeutic uses. Thus, PGS are used in the treatment of asthma and circulatory diseases because PGS of the E-type have vessel-dilatating activity. On the other hand, PGS induce labor and initiate parturition so that they possibly can be used for inducing abortion.
It was not known until recently that the activity of some medicaments with analgesic and anti-inflammatory action which had already been used for decades is based on an inhibition of the prostaglandin synthetases. This applies for e.g. acetylosalicylic acid, indometacine or ibuprofen. The strong inhibitory action of these compounds explains the activity against inflammations on the one hand and on the other hand the presence of several side effects of which only the induction of stomach hemmorrhages is referred to.
The biosynthesis of the PGS starts from membrane phospholipides which are converted into arachidonic acid and are reacted into endoperoxide-PGS by oxygen radicals. By further reactions the relatively stable PGS, thromboxanes and the relatively instable prosta-cyclin are formed of the endoperoxide-PGS.
The synthesis of PGE.sub.2 and PGF.sub.2..alpha. from arachidonic acid can be shown in a shortened way in the following formula: ##STR1## The biological residence time of PGS and their precursors is only miniscule. The decomposition starts from oxidation at C-5 and continues via the .beta.-oxidation of fatty acids.
It has already been established that certain chemical compounds are strong PGS inhibitors. These compounds e.g. indometacine of acetylosalicylic acid had been found to be PGE.sub.2 -synthetase inhibitors and are used correspondingly in the treatment of rheumatic and arthritic and similar conditions for instance. The strong inhibitor action which is not necessarily restricted to PGE.sub.2 -synthetase leads to unwanted side effects based on this action e.g. initiations of bleedings in the stomach and intestine, other scattered bleedings, occurrence of allergies or possibilities of influencing gravidity.
Therefore, it is the object of the invention to develop a new medicament with an activity as a PGS-inhibitor which does not possess the known disadvantages.